Carbon monoxide stimulates mrp2-dependent excretion of bilirubin-IXα into bile in the perfused rat liver

Shinji Norimizu, Atsushi Kudo, Mayumi Kajimura, Kazuo Ishikawa, Hisashi Taniai, Tokio Yamaguchi, Kimihito Fujii, Shigeki Arii, Yuji Nimura, Makoto Suematsu

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19 Citations (Scopus)


Although carbon monoxide (CO) has been reported to protect against hepatobiliary dysfunction, mechanisms for its actions remain unknown. This study aimed to examine actions of physiologically relevant concentrations of CO on biliary excretion. The effects of transportal administration of CO on bile output and constituents were examined in perfused rat livers. In livers of fed rats, CO regulated bile output biphasically in a dose-dependent manner; transportal administration of CO at 4 μmol/L stimulated bile output by 10%. Under these circumstances, CO increased paracellular junctional permeability and consequently decreased biliary excretion of bile salts. Choleresis elicited by 4 μmol/L CO coincided with significant increases in biliary excretion of bilirubin-IXα and glutathione. The CO-induced choleresis occurred independently of cyclic GMP, co-incided with elevated excretion of K + and HCO3-, and was abolished by tetraethylammonium, suggesting stimulatory effects of the gas on potassium channels. CO-mediated choleresis and increased excretion of organic anions appeared to be mediated by mrp2, because Eisai hyperbilirubinemia rats, which genetically lack the transporter, did not exhibit choleresis upon the CO administration. These results suggest that CO stimulates mrp2-dependent excretion of bilirubin-IXα through mechanisms involving potassium channels, serving as a cooperator standing behind the heme oxygenase reaction to facilitate hepatic heme detoxification.

Original languageEnglish
Pages (from-to)449-456
Number of pages8
JournalAntioxidants and Redox Signaling
Issue number4
Publication statusPublished - 2003 Aug

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology


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